Abstract
Background:
Exchange transfusion is commonly used in newborns for immediate treatment of severe hyperbilirubinemia to prevent bilirubin encephalopathy and kernicterus.Objectives:
This study aimed to determine etiology and complications in newborns who received exchange transfusion for severe hyperbilirubinemia over the last five years.Patients and Methods:
A retrospective study was performed on 28 days old infants who received exchange transfusion due to severe hyperbilirubinemia for a period of five years (from October 1st, 2006 through September 30th, 2011) in two neonatal units at Besat and Fatemieh hospitals in Hamadan, Iran. All data about patients’ demographic characteristics, causes of hyperbilirubinemia, frequency, and complications of exchange transfusion were collected from medical records and analyzed using SPSS Version 12.0).Results:
Exchange transfusion was performed in 148 neonates. Eighteen patients (12.2%) received exchange transfusion twice and seventeen patients (11.4%) three times or more. Among 118 neonates 80 (54.9%) were female and the mean gestational age and birth weight were 37.2 ± 2.5 weeks and 2847 ± 699 grams, respectively. The mean maximum total serum bilirubin levels were 27. 7.6 ± 7.28 mg/dL. Hemolytic disease was found in 72 (48.6%) of newborns. The most common cause of hemolysis was ABO incompatibility in 54 (36.5%). The etiologic factors were unidentified in 61 (41.2%) neonates. Complications occurred in 57 (38.5%) neonates and the most common complications were thrombocytopenia in 26 (17.6%) and hypocalcaemia in 17 (11.5%) neonates. Mortality was found in one (0.7%) neonate.Conclusions:
The etiology of exchange transfusion was unidentified in most cases; however, ABO incompatibility was the most prevalent cause of hyperbilirubinemia. Complications were common after exchange transfusion and should be considered carefully.Keywords
Hyperbilirubinemia Exchange Transfusion Whole Blood Complications Infant Newborn
1. Background
About 60% of term and 80% of preterm infants have clinical jaundice in the first week after birth but only 0.02 to 0.16% of them develop severe hyperbilirubinemia (Total Serum Bilirubin (TSB) > 25 mg/dL), which is an emergency because it may cause neonatal bilirubin encephalopathy, which can result in death or irreversible brain damage in survivor (1-3). Intensive phototherapy and exchange transfusion (ET) play important roles in the treatment of severe hyperbilirubinemia of newborns to prevent bilirubin encephalopathy (4). Although the value of exchange transfusion in the treatment of neonatal hyperbilirubinemia is recognized, the bilirubin levels in which ET is necessary remained a matter of disagreement (5-7). ET is effective and considered to be a safe procedure; however, it is not without risks and complications have been reported and mortality rates vary from 0.5 to 3.3%. Therefore, the current recommendations for performing ET are based on balance between the risks of encephalopathy and adverse events related to the procedure (8, 9). Complications of ET may be increased by the amount of blood exchanged. Most of these complications are asymptomatic and transient, such as severe thrombocytopenia, apnea, hypocalcemia, bradycardia, and hyperkalemia, but life threatening infections and even death can occur within seven days after the exchange (10-13).
2. Objectives
The purpose of this study was to investigate the etiology and complications of exchange blood transfusion in a patient population visited in our center over the last five years.
3. Patients and Methods
The medical records of infants, 28 day old, who received exchange transfusion due to severe hyperbilirubinemia in neonatal units at Besat and Fatemieh university hospitals in Hamadan for a period of five years (from October 1st 2006 through September 30th, 2011 ) were reviewed retrospectively. Exchange transfusion was performed by pediatric residents under direct supervision of pediatric professor. The double volume exchange method (170 mg/kg) was completed for approximately 1 - 2 hours by repeatedly removing and replacing a small amount of blood (5 mL/kg) according to standard practice guidelines. Infants’ heart rate and oxygen saturation were monitored during exchange transfusion.
Laboratory investigations were performed such as complete blood counts, direct and total bilirubin, erythrocyte glucose -6- phosphate dehydrogenase (G6PD) level, direct coombs test, maternal and baby blood groups, serum calcium, glucose, sodium, potassium, and blood cultures before and after the exchange.
Intravenous calcium gluconate was used during exchange transfusion to neutralize the effect of citrate in Citrate Phosphate Dextrose Adenine (CPDA) solution. All episodes of complication were recorded up to three days after exchange transfusion. The definition of complications used were as hypoglycemia when serum glucose was < 50 mg/dL, hypocalcemia if serum calcium was < 8 mg/dL (for preterm newborn, 7 mg/dL), hyperkalemia when serum potassium was > 6 meq/dL, thrombocytopenia when platelet count was < 100.000/mm3, bradycardia if heart rate was < 80 beat/minute, apnea cessation of respiration for > 20 seconds, seizure any tonic or clonic movement, necrotizing enterocolitis defined as per bell's criteria. Complications of severe neonatal hyperbilirubinemia, consisting of kernicterus were not included in this study. Exclusion criteria were incomplete records of patients and those older than 28 days old. Statistical analysis was performed using SPSS Version 12.0 (SPSS, Inc, Chicago, USA).
4. Results
There were 6108 neonatal admissions due to neonatal jaundice that exchange transfusion was performed in 148 neonates (2.4%). Among them 68 (45.1%) were male and 80 (54.9%) female. Mean birth weight was 2847 ± 699 grams and mean gestational age of neonates was 37.2 ± 2.5 weeks. Overall, 102 (68.9%) infants were term and 46 (31.1%) preterm. The mean maximum total serum bilirubin was 27.76 ± 7.28 mg/dL and the mean age of exchange transfusion was 4.97 ± 2.65 days (Table 1).
Baseline Demographic Characteristics a
| Characteristic | Value |
|---|---|
| Gender | |
| Male | 68 (45.1) |
| Female | 80 (54.9 ) |
| Gestational Age Group | |
| Term | 102 (68.9) |
| Preterm | 46 (31.1) |
| Gestational age, wk | 37.2 ± 2.5 |
| Maximum total serum bilirubin, mg/dL | 27.76 ± 7.28 |
| Age at exchange transfusion, d | 4. 97 ± 2.65 |
| Frequency of Exchange Transfusion | |
| One | 113 (76.4) |
| Two | 18 (12.2) |
| Three | 17 (11.4) |
| Complication rate | 57 (38.5) |
| Duration of hospital stay, d | 6.79 ± 6.64 |
Among 148 cases, no etiologic factors were identified in 61 (41.2%) neonates, ABO incompatibility was found in 54 (36.5%), RH incompatibility in 15 (10.1%) and G6PD deficiency in 14 (9.5%) neonates (Table 2). During and immediately after exchange transfusion, 57 (38.5%) neonates developed complications. Most complications were thrombocytopenia (17.6%), hypocalcemia (11.5%), hypoglycemia (9.5%), hyperkalemia (5.4%), hyponatremia (4.1%), apnea (4.7%), and septicemia (2%). One (0.7%) neonate died of complications probably attributable to exchange transfusion (Table 3). Comparing variables between term and preterm infants showed no significant difference in complications between the two groups (Tables 4 and 5).
Etiology of Neonatal Hyperbilirubinemia
| Causes | NO (%) |
|---|---|
| ABO incompatibility | 54 (36.5) |
| RH incompatibility | 15 (10.1) |
| ABO and RH incompatibility | 3 (2.0) |
| G6PD deficiency | 14 (9.5) |
| Polycythemia | 1 (0.7) |
| Unidentified | 61 (41.2) |
| Total | 148 (100) |
Complications of Exchange Transfusion
| Complications | No (%) |
|---|---|
| Thrombocytopenia | 26 (17.6) |
| Hypocalcemia | 17 ( 11.5) |
| Hypoglycemia | 14 (9.5) |
| Hyperkalemia | 8 (5.4) |
| Hyponatremia | 6 (4.1) |
| Bradycardia | 12 (8.1) |
| Apnea | 7 (4.7) |
| Necrotizing enterocolitis | 3 (2) |
| Septicemia | 3 (2) |
| DIC | 2 (1.4) |
| Cardiorespiratory arrest | 2 (1.4) |
| Death | 1 (0.7) |
Comparing Variables Between Term and Preterm Infants a
| Variables | Term 102 (68.9) | Preterm 46 (31.1) | P Value |
|---|---|---|---|
| Gender | 0.374 | ||
| Male | 44 (43.1) | 24 (52.2) | |
| Female | 58 (56.9) | 22 (47.8) | |
| Causes | 0.171 | ||
| ABO incompatibility | 42 (41.2) | 12 (26.1) | |
| RH incompatibility | 11 (10.8) | 4 (8.7) | |
| ABO&RH incompatibility | 2 (2) | 1 (2.2) | |
| G6PD deficiency | 11 (10.8) | 3 (6.5) | |
| Polycythemia | 0 (0.0) | 1 (2.2) | |
| Unidentified | 36 (35.6) | 25 (54.3) | |
| Complications | 0.529 | ||
| Yes | 39 (38.2) | 18 (39.1) | |
| No | 63 (61.8) | 28 (60.9) | |
| Thrombocytopenia | 0.400 | ||
| Yes | 19 (18.6) | 7 (15.2) | |
| No | 83 (81.4) | 39 (84.8) | |
| Hypocalcemia | 0.160 | ||
| Yes | 14 (13.7) | 3 (6.5) | |
| No | 88 (86.3) | 43 (93.5) | |
| Hypoglycemia | 0.238 | ||
| Yes | 8 (7.8) | 6 (13.0) | |
| No | 94 (92.2) | 40 (87.0) | |
| Hyperkalemia | 0.523 | ||
| Yes | 6 (5.9) | 2 (4.3) | |
| No | 96 (94.1) | 44 (95.7) | |
| Hyponatremia | 0.273 | ||
| Yes | 3 (2.9) | 3 (6.5) | |
| No | 99 (97.1) | 43 (93.5) | |
| Bradycardia | 0.545 | ||
| Yes | 8 (7.8) | 4 (8.7) | |
| No | 94 (92.2) | 42 (91.3) | |
| Apnea | 0.131 | ||
| Yes | 3 (2.9) | 4 (8.7) | |
| No | 99 (97.1) | 42 (91.3) | |
| Necrotizing enterocolitis | 0.232 | ||
| Yes | 1 (1.0) | 2 (4.3) | |
| No | 101 (99.0) | 44 (95.7) | |
| Septicemia | 0.324 | ||
| Yes | 3 (2.9) | 0 (0.0) | |
| No | 99 (97.1) | 46 (100.0) | |
| DIC | 0.526 | ||
| Yes | 1 (1.0) | 1 (2.2) | |
| No | 101 (99.0) | 45 (97.8) | |
| Cardiorespiratory arrest | 0.526 | ||
| Yes | 1 (1.0) | 1 (2.2) | |
| No | 101 (99.0) | 45 (97.8) | |
| Death | 0.689 | ||
| Yes | 1 (1.0) | 0 (0.0) | |
| No | 101 (99.0) | 46 (100.0) |
Comparing Variables With and Without Complications
| Variables | Complications | P Value | |
|---|---|---|---|
| Yes = 57 (38.5) | No = 89 (61.5) | ||
| Gender a | 0.341 | ||
| Male | 29 (42.6) | 39 (57.4) | |
| Female | 28 (35.0) | 52 (65.0) | |
| Gestational age group a | 0.918 | ||
| Term | 39 (38.2) | 63 (61.8) | |
| Preterm | 18 (39.1) | 28 (60.9) | |
| Gestational age, wk b | 36.8 ± 3.0 | 37.5 ± 2.0 | 0.120 |
| Birth weight, g b | 2771 ± 764 | 2894 ± 656 | 0.299 |
| Admission age, d b | 4.6 ± 3.9 | 4.4 ± 2.3 | 0.844 |
| Maximum total Serum bilirubin, mg/dL b | 28.8 ± 8.6 | 27.1 ± 6.3 | 0.167 |
| Causes a | 0.145 | ||
| ABO incompatibility | 15 (27.8) | 39 (72.2) | |
| RH incompatibility | 8 (53.3) | 7 (46.7) | |
| ABO&RH incompatibility | 2 (66.7) | 1 (33.3) | |
| G6PD deficiency | 4 (28.6) | 10 (71.4) | |
| Polycythemia | 0 (0.0) | 1 (100.0) | |
| Unidentified | 28(45.9) | 33(54.1) | |
| Hospital stay, d b | 9.0 ± 7.2 | 5.3 ± 5.8 | 0.001 |
5. Discussion
Exchange blood transfusion has reminded the gold standard for rapid lowering higher level serum bilirubin concentration and prevention of bilirubin encephalopathy and kernicterus. Although reports show progressive decline over the years in number of neonates who need exchange transfusion because of anti-Rh globulin for mothers and widespread use of phototherapy for neonatal jaundice, it is still required in up to 7% of neonates admitted to nurseries (13).
Despite advances in neonatal care in the recent years, exchange transfusion still remains a high risk procedure with common adverse effects. We observed a high rate of complications associated with exchange transfusion in 57 (38.5%) neonates; however, most of these were asymptomatic and transient. Most common complications in our study were thrombocytopenia (17.6%), hypocalcemia (11.5%), hypoglycemia (9.5%), hyperkalemia (5.4%), and hyponatremia (4.1%), which are similar to the findings of most previous studies (14, 15). Similarly, the rate of serious complication such as necrotizing enterocolitis and septicemia from ET is very low, approximately 1% and prior reports indicated that necrotizing enterocolitis and septicemia are the most common severe complications (11, 12, 16, 17).
Other serious complications of our study were apnea and bradycardia observed in 4.7% and 8.4% of neonates, respectively. Mortality directly attributable to exchange transfusion is reported to be at least 1% and is due to unexplained cardiac arrest, cardiac arrhythmias or air embolism (18). We observed a mortality of 1.4%; while, other studies reported a mortality rate range from 0.66% to 3.2% and (10, 12, 16, 19) Chime and Davutoglu reported no death in their study (20, 21).
Because many complications of exchange transfusion are unavoidable even with careful monitoring, early diagnosis of severe hyperbilirubinemia and phototherapy is the best way to reduce these complications that reduce the need for exchange transfusion in turn.
Multiple exchange transfusion was required in 23.6% of our neonates, which is similar to the findings of Dikshit (22), but more than Abu-Ekteish et al. (23). In our study, no etiologic factors were identified in 61 (41.2%) neonates, a rate reported previously as 17 - 40% (16, 24-27) and ABO incompatibility was observed in 54 (36.5%) neonates, which is similar to other studies (28-30). Rh incompatibility alone or concomitant with ABO incompatibility was observed in 15 (10.1%) and 3 (2.0%) neonates, respectively. The reduction in Rh incompatibility may be due to the use of anti-Rh globulin for Rh negative mothers (31). G6PD deficiency accounted for 14 (9.5%) of all causes of ET in our study. This figure is lesser than Badiee’s study (12), which estimated 19% prevalence of G6PD deficiency and higher than Bhat et al. (32) who reported no patient with G6PD deficiency. This difference in prevalence could be due to racial differences in the prevalence of G6PD deficiency.
This report indicated that complications are common after exchange transfusion despite technological advances in neonatal care and careful monitoring. Therefore, early recognition of infants at risk of severe hyperbilirubinemia and the use of intensive phototherapy can significantly reduce the need of exchange transfusion.
Acknowledgements
References
-
1.
Bhutani VK, Johnson LH, Keren R. Diagnosis and management of hyperbilirubinemia in the term neonate: for a safer first week. Pediatr Clin North Am. 2004;51(4):843-61. vii. [PubMed ID: 15275978]. https://doi.org/10.1016/j.pcl.2004.03.011.
-
2.
Ebbesen F, Andersson C, Verder H, Grytter C, Pedersen-Bjergaard L, Petersen JR, et al. Extreme hyperbilirubinaemia in term and near-term infants in Denmark. Acta Paediatr. 2005;94(1):59-64. [PubMed ID: 15858962].
-
3.
Hansen TW. Kernicterus in term and near-term infants--the specter walks again. Acta Paediatr. 2000;89(10):1155-7. [PubMed ID: 11083367].
-
4.
Smitherman H, Stark AR, Bhutani VK. Early recognition of neonatal hyperbilirubinemia and its emergent management. Semin Fetal Neonatal Med. 2006;11(3):214-24. [PubMed ID: 16603425]. https://doi.org/10.1016/j.siny.2006.02.002.
-
5.
Watchko JF, Oski FA. Bilirubin 20 mg/dL = vigintiphobia. Pediatrics. 1983;71(4):660-3. [PubMed ID: 6682217].
-
6.
Newman TB, Maisels MJ. Evaluation and treatment of jaundice in the term newborn: a kinder, gentler approach. Pediatrics. 1992;89(5 Pt 1):809-18. [PubMed ID: 1579380].
-
7.
Practice parameter: management of hyperbilirubinemia in the healthy term newborn. American Academy of Pediatrics. Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia. Pediatrics. 1994;94(4 Pt 1):558-65. [PubMed ID: 7755691].
-
8.
Bowman J. The management of hemolytic disease in the fetus and newborn. Semin Perinatol. 1997;21(1):39-44. [PubMed ID: 9190032].
-
9.
Philip AG. The rise and fall of exchange transfusion. Neo Reviews. 2003;4:169-74.
-
10.
Ip S, Chung M, Kulig J, O'Brien R, Sege R, Glicken S, et al. An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics. 2004;114(1):e130-53. [PubMed ID: 15231986].
-
11.
Jackson JC. Adverse events associated with exchange transfusion in healthy and ill newborns. Pediatrics. 1997;99(5):E7. [PubMed ID: 9113964].
-
12.
Badiee Z. Exchange transfusion in neonatal hyperbilirubinaemia: experience in Isfahan, Iran. Singapore Med J. 2007;48(5):421-3. [PubMed ID: 17453099].
-
13.
Funato M, Tamai H, Shimada S. Trends in neonatal exchange transfusions at Yodogawa Christian Hospital. Acta Paediatr Jpn. 1997;39(3):305-8. [PubMed ID: 9241889].
-
14.
Hoontrakoon S, Suputtamongkol Y. Exchange transfusion as an adjunct to the treatment of severe falciparum malaria. Trop Med Int Health. 1998;3(2):156-61. [PubMed ID: 9537279].
-
15.
Patra K, Storfer-Isser A, Siner B, Moore J, Hack M. Adverse events associated with neonatal exchange transfusion in the 1990s. J Pediatr. 2004;144(5):626-31. [PubMed ID: 15126997]. https://doi.org/10.1016/j.jpeds.2004.01.054.
-
16.
BulBul A, Okan FF, Kabakoglu Unsur, E, Nuhoglu, A. Adverse events associated with exchange transfusion and etiology of severe hyperbilirubinemia in near-term andterm newborns. Turk J Med Sci. 2011;41(1):93-100.
-
17.
Hovi L, Siimes MA. Exchange transfusion with fresh heparinized blood is a safe procedure. Experiences from 1 069 newborns. Acta Paediatr Scand. 1985;74(3):360-5. [PubMed ID: 4003059].
-
18.
Bohggs TR. Westphal MC Mortality of exchange trans-fusion Pediatrics. Pediatrics. 1960;26(5):745-55.
-
19.
Panagopoulos G, Valaes T, Doxiadis SA. Morbidity and mortality related to exchange transfusions. J Pediatr. 1969;74(2):247-54. [PubMed ID: 5782912].
-
20.
Chima RS, Johnson LH, Bhutani VK. Evaluation of adverse events due to exchange transfusion in term and near-term newborns. Pediatr Res. 2001;49:324.
-
21.
Davutoglu M, Garipardic M, Guler E, Karabiber H, Erhan D. The etiology of severe neonatal hyperbilirubinemia and complications of exchange transfusion. Turk J Pediatr. 2010;52(2):163-6. [PubMed ID: 20560252].
-
22.
Dikshit SK, Gupta PK. Exchange transfusion in neonatal hyperbilirubinemia. Indian Pediatr. 1989;26(11):1139-45. [PubMed ID: 2630476].
-
23.
Abu-Ekteish F, Daoud A, Rimawi H, Kakish K, Abu-Heija A. Neonatal exchange transfusion: a Jordanian experience. Ann Trop Paediatr. 2000;20(1):57-60. [PubMed ID: 10824215].
-
24.
Sanpavat S. Exchange transfusion and its morbidity in ten-year period at King Chulalongkorn Hospital. J Med Assoc Thai. 2005;88(5):588-92. [PubMed ID: 16149673].
-
25.
Saxena A, Bairwa AL. Indications and Complications of Exchange Transfusion in A Tertiary. Indian J Res. 2014;3(3):12-3.
-
26.
Narang A, Gathwala G, Kumar P. Neonatal jaundice: an analysis of 551 cases. Indian Pediatr. 1997;34(5):429-32. [PubMed ID: 9332119].
-
27.
Begum S, Baki MA, Kundu G, Islam I, Talukdar MK, Fatema K. Exchange Transfusion: Indication and Adverse Effect. Bangladesh Journal of Child Health. 2012;36(1):16-9.
-
28.
Drabik-Clary K, Reddy VV, Benjamin WH, Boctor FN. Severe hemolytic disease of the newborn in a group B African-American infant delivered by a group O mother. Ann Clin Lab Sci. 2006;36(2):205-7. [PubMed ID: 16682519].
-
29.
Huizing K, Roislien J, Hansen T. Intravenous immune globulin reduces the need for exchange transfusions in Rhesus and AB0 incompatibility. Acta Paediatr. 2008;97(10):1362-5. [PubMed ID: 18616629].
-
30.
Sgro M, Campbell D, Shah V. Incidence and causes of severe neonatal hyperbilirubinemia in Canada. CMAJ. 2006;175(6):587-90. [PubMed ID: 16966660]. https://doi.org/10.1503/cmaj.060328.
-
31.
Woodrow JC. Effectiveness of Rh prophylaxis. Haematologia (Budap). 1974;8(1-4):281-90. [PubMed ID: 4218822].
-
32.
Bhat AW, Churoo BA, Iqbal Q, Sheikh MA, Iqbal J, Aziz R. Complication of exchange transfusion at a tertiary care hospital. Current Pediatric Research. 2011;15(2).